Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells

Nonactivated CD4+CD25+ regulatory T cells constitutively express glucocorticoid-induced TNFR family-related receptor (GITR), a TNFR family member whose engagement was presumed to abrogate regulatory T cell-mediated suppression. Using GITR−/− mice, we report that GITR engagement on CD25−, not CD25+ T cells abrogates T cell-mediated suppression. Mouse APCs constitutively express GITR ligand (GITR-L), which is down-regulated following TLR signaling in vivo. Although GITR−/−CD25− T cells were capable of mounting proliferative responses, they were incapable of proliferation in the presence of physiological numbers of CD25+ T cells. Thus, GITR-L provides an important signal for CD25− T cells, rendering them resistant to CD25+-mediated regulation at the initiation of the immune response. The down-regulation of GITR-L by inflammatory stimuli may enhance the susceptibility of effector T cells to suppressor activity during the course of an infectious insult.

[1]  J. Bluestone,et al.  Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells 1 , 2003, The Journal of Immunology.

[2]  H. Waldmann,et al.  Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Ethan M. Shevach,et al.  Cutting Edge: IL-2 Is Critically Required for the In Vitro Activation of CD4+CD25+ T Cell Suppressor Function , 2004, The Journal of Immunology.

[4]  A. Gurney,et al.  Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR , 1999, Current Biology.

[5]  A. Rudensky,et al.  Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo , 2002, Nature Immunology.

[6]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[7]  T. Waldmann,et al.  Interleukin 2 (IL-2) augments transcription of the IL-2 receptor gene. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[8]  H. Macdonald,et al.  The Early IL-4 Response to Leishmania major and the Resulting Th2 Cell Maturation Steering Progressive Disease in BALB/c Mice Are Subject to the Control of Regulatory CD4+CD25+ T Cells1 , 2002, The Journal of Immunology.

[9]  S. Miller,et al.  Cutting Edge: Ligation of the Glucocorticoid-Induced TNF Receptor Enhances Autoreactive CD4+ T Cell Activation and Experimental Autoimmune Encephalomyelitis1 , 2004, The Journal of Immunology.

[10]  P. Blair,et al.  CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-X(L) induction. , 1998, Journal of immunology.

[11]  M. Croft.  Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? , 2003, Nature Reviews Immunology.

[12]  Ethan M. Shevach,et al.  CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production , 1998, The Journal of experimental medicine.

[13]  A. Svennerholm,et al.  Helicobacterpylori-Specific CD4+ CD25high Regulatory T Cells Suppress Memory T-Cell Responses to H. pylori in Infected Individuals , 2003, Infection and Immunity.

[14]  Tetsuya Nakamura,et al.  Regulation of Murine Inflammatory Bowel Disease by CD25+ and CD25− CD4+ Glucocorticoid-Induced TNF Receptor Family-Related Gene+ Regulatory T Cells1 , 2003, The Journal of Immunology.

[15]  S. Song,et al.  Identification of a ligand for glucocorticoid-induced tumor necrosis factor receptor constitutively expressed in dendritic cells. , 2003, Biochemical and biophysical research communications.

[16]  幸治 浦牛原.  Regulation of murine inflammatory bowel disease by CD25[+] and CD25[-]CD4[+] glucocorticoid-induced TNF receptor family-related gene[+] regulatory T cells , 2004 .

[17]  M. Toda,et al.  Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. , 1998, International immunology.

[18]  M. Gunn,et al.  Cd11c+B220+Gr-1+ Cells in Mouse Lymph Nodes and Spleen Display Characteristics of Plasmacytoid Dendritic Cells , 2001, The Journal of experimental medicine.

[19]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[20]  M. Byrne,et al.  CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. , 2002, Immunity.

[21]  E. Shevach,et al.  Cutting Edge: Control of CD8+ T Cell Activation by CD4+CD25+ Immunoregulatory Cells , 2001, The Journal of Immunology.

[22]  Guo-liang Yu,et al.  Identification of a Novel Activation-inducible Protein of the Tumor Necrosis Factor Receptor Superfamily and Its Ligand* , 1999, The Journal of Biological Chemistry.

[23]  P. Pandolfi,et al.  Role of GITR in activation response of T lymphocytes. , 2002, Blood.

[24]  P. Blair,et al.  Cutting Edge: CTLA-4 Ligation Delivers a Unique Signal to Resting Human CD4 T Cells That Inhibits Interleukin-2 Secretion but Allows Bcl-XL Induction , 1998, The Journal of Immunology.

[25]  J. Ashwell,et al.  Interleukin 2 upregulates expression of its receptor on a T cell clone , 1985, The Journal of experimental medicine.

[26]  Y. Belkaid,et al.  CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity , 2002, Nature.

[27]  P. Rogers,et al.  OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. , 2001, Immunity.

[28]  J. Lafaille,et al.  Interleukin 2 Signaling Is Required for CD4+ Regulatory T Cell Function , 2002, The Journal of experimental medicine.

[29]  H. Okada,et al.  Escape of malaria parasites from host immunity requires CD4+CD25+ regulatory T cells , 2004, Nature Medicine.

[30]  E. Coligan.  Current protocols in immunology , 1991 .

[31]  A. Zlotnik,et al.  A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. , 1993, Journal of immunology.

[32]  B. Kwon,et al.  Cloning and characterization of GITR ligand , 2003, Genes and Immunity.

[33]  Nigel J. Saunders,et al.  CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms , 2003, The Journal of experimental medicine.

[34]  S. Kaufmann,et al.  Regulatory CD4+CD25+ T Cells Restrict Memory CD8+ T Cell Responses , 2002, The Journal of experimental medicine.

[35]  K. Shortman,et al.  Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. , 1997, Journal of immunology.

[36]  C. Riccardi,et al.  Frontline: GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations , 2004, European journal of immunology.

[37]  C. Thompson,et al.  Expression of the costimulatory receptor CD30 is regulated by both CD28 and cytokines. , 1998, Journal of immunology.

[38]  E. Shevach,et al.  The role of suppressor T cells in regulation of immune responses. , 2002, The Journal of allergy and clinical immunology.

[39]  W. Faubion,et al.  Cutting Edge: The Natural Ligand for Glucocorticoid-Induced TNF Receptor-Related Protein Abrogates Regulatory T Cell Suppression 1 , 2004, The Journal of Immunology.

[40]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[41]  W. Ouyang,et al.  Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. , 1998, Immunity.

[42]  B. Rouse,et al.  CD4+CD25+ T Cells Regulate Virus-specific Primary and Memory CD8+ T Cell Responses , 2003, The Journal of experimental medicine.

[43]  J. Shimizu,et al.  Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance , 2002, Nature Immunology.